Hyperfiltration-associated biomechanical forces in glomerular injury and response: Potential role for eicosanoids

Abstract

Hyperfiltration is a well-known risk factor in progressive loss of renal function in chronic kidney disease (CKD) secondary to various diseases. A reduced number of functional nephrons due to congenital or acquired cause(s) results in hyperfiltration in the remnant kidney. Hyperfiltration-associated increase in biomechanical forces namely pressure-induced tensile stress and fluid flow-induced shear stress (FFSS) determine cellular injury and response. We believe the current treatment of CKD yields limited success because it largely attenuates pressure-induced tensile stress changes but not the effect of FFSS on podocytes. Studies on glomerular podocytes, tubular epithelial cells and bone osteocytes provide evidence for a significant role of COX-2 generated PGE2 and its receptors in response to tensile stress and FFSS. Preliminary observations show increased urinary PGE2 in children born with a solitary kidney. FFSS-induced COX2-PGE2-EP2 signaling provides an opportunity to identify targets and, for developing novel agents to complement currently available treatment.

Cyclooxygenase (COX)-2 Inhibitors Reduce Toxoplasma gondii Infection and Upregulate the Pro-inflammatory Immune Response in Calomys callosus Rodents and Human Monocyte Cell Line

“…Prostaglandins are lipid mediators able to regulate many functions during an inflammation, such as cytokine production and cellular activation/maturation (Nagamatsu and Schust, 2010; Kalinski, 2012). The production of PGE 2 occurs when arachidonic acid is converted into prostaglandins by enzymes called cyclooxygenases, as previously described (Batlouni, 2010; Agard et al, 2013; Sharma et al, 2017; Martínez-Colón and Moore, 2018). Many studies demonstrate the role of COX-2 and PGE 2 during infections triggered by pathogens (Michelin et al, 2005; Abdalla et al, 2008; Tatakihara et al, 2008; Moraes et al, 2015), however there are no studies demonstrating association between COX-2 and susceptibility to T. gondii infection.…”

“…Subsequently, the arachidonic acid is converted into prostaglandins by enzymes called cyclooxygenases (COXs). There are at least two isoforms of COX: COX-1, constitutively expressed in all cell types, and COX-2, which is induced by inflammatory mediators, mainly cytokines (Batlouni, 2010; Agard et al, 2013; Sharma et al, 2017; Martínez-Colón and Moore, 2018).…”

Mechanotransduction signaling in podocytes from fluid flow shear stress

“…These include the changes in podocyte structure/function and consequential loss of glomerular filtration barrier resulting in albuminuria. Therefore we and others have started reconsidering hyperfiltration in terms of biomechanical forces within the glomerulus (30,31,48,54). We believe that investigating the effect of biomechanical forces on podocytes within the glomerulus may provide a better understanding of hyperfiltration-mediated kidney injury.…”

Hyperfiltration-mediated Injury in the Remaining Kidney of a Transplant Donor

“…However, in contrast to mesangial and endothelial cells, podocytes are terminally differentiated cells with low mitotic potential. Changes in the capillary pressure and the flow of the glomerular ultrafiltrate subject podocytes to pressure and flow-associated biomechanical forces that may result in their detachment [90-93]. These rheological factors and the inability to replace the lost cells render podocytes the most vulnerable component of the glomerular filtration barrier vis- à-vis mesangial and endothelial cells.…”

“…Blood flow through capillary loops generates force radially at 90° to the direction of flow, causing the capillary wall to stretch and dilate which, in turn, radiates the force to podocyte foot processes attached to the GBM on the outer aspect of the capillary (Figure 1). Glomerular capillary pressure within the vascular compartment is the major determinant of tensile stress exerted over the basolateral aspect of podocytes [90,94]. The stretch on podocyte foot processes attached to the GBM results in tensile stress on podocytes.…”